Robust Amyloid Clearance in a Mouse Model of Alzheimer's Disease Provides Novel Insights into the Mechanism of Amyloid-β Immunotherapy

Many new therapeutics for Alzheimer's disease delay the accumulation of amyloid-beta (A beta) in transgenic mice, but evidence for clearance of preexisting plaques is often lacking. Here, we demonstrate that anti-A beta immunotherapy combined with suppression of A beta synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP (amyloid precursor protein) mice with doxycycline to suppress transgenic A beta production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterward to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and A beta 42 content by 28% relative to pretreatment levels, with preferential clearance of small deposits and diffuse A beta surrounding fibrillar cores. We demonstrate that peripherally administered anti-A beta antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma A beta levels, where it enhanced microglial internalization of aggregated A beta. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated A beta, but is opposed by the continued aggregation of newly secreted A beta. By arresting the production of A beta, combination therapy allows microglial clearance to work from a static amyloid burden toward a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone.